Nicotine-induced changes in cerebrocortical neuroactive steroids and plasma corticosterone concentrations in the rat

Porcu, Patrizia; Sogliano, Cristiana; Cinus, Monica; Purdy, Robert H.; Biggio, Giovanni; Concas, Alessandra

doi:10.1016/s0091-3057(02)01065-1

Cited by 62 publications

(51 citation statements)

References 40 publications

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“…For THDOC, recent estimates of the basal plasma concentration in male rats range from Ϸ5 to 8 nM (26)(27)(28), to nearly 20 nM after acute swim stress (26). As shown in Fig.…”

Section: Resultsmentioning

confidence: 91%

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors

Stell

Brickley

Tang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

743

793

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Neuroactive steroids are potent modulators of ␥-aminobutyric acid type A receptors (GABA ARs), and their behavioral effects are generally viewed in terms of altered inhibitory synaptic transmission. Here we report that, at concentrations known to occur in vivo, neuroactive steroids specifically enhance a tonic inhibitory conductance in central neurons that is mediated by extrasynaptic ␦ subunit-containing GABAARs. The neurosteroid-induced augmentation of this tonic conductance decreases neuronal excitability. Fluctuations in the circulating concentrations of endogenous neuroactive steroids have been implicated in the genesis of premenstrual syndrome, postpartum depression, and other anxiety disorders. Recognition that ␦ subunit-containing GABAARs responsible for a tonic conductance are a preferential target for neuroactive steroids may lead to novel pharmacological approaches for the treatment of these common conditions. hippocampus ͉ cerebellum ͉ neurosteroids ͉ inhibitory postsynaptic currents ͉ ␦ knockout mice G ABA A Rs (␥-aminobutyric acid type A receptors) are pentameric proteins that form Cl Ϫ -permeable ion channels activated by the neurotransmitter GABA. To date, 19 mammalian GABA A subunit isoforms have been identified, and these assemble to produce the dozen or so different receptor subtypes most frequently found in the brain (1). The most potent positive endogenous modulators of GABA A R function are the 3␣-hydroxy ring A-reduced pregnane steroids, that have sedativehypnotic, anticonvulsant, and anxiolytic effects (2-4). Severe mood disorders that can occur during the menstrual cycle and after pregnancy are suggested to involve alterations in the function of synaptic GABA A Rs (2, 3, 5) triggered by rapid decreases in the concentrations of these progesterone-derived neuroactive steroids (6).Recently, it has become apparent that distinct GABA A Rs participate in two types of inhibitory control. Transient activation of synaptic GABA A Rs is responsible for conventional phasic inhibition, whereas the continuous activation of extrasynaptic GABA A Rs can generate a form of tonic inhibition (7-14). GABA A Rs containing the ␦ subunit are restricted to extrasynaptic locations (15) and have an unusually high affinity for GABA (16,17), making them likely mediators of the tonic GABA A conductance recorded in both cerebellar (7,8) and dentate gyrus granule cells (DGGC) (10, 11). In mice lacking the ␦ subunit of the GABA A R, the effects of neuroactive steroids are greatly reduced (18). Moreover, recent reports (17,19,20) have raised the possibility that the steroid sensitivity of ␦ subunitcontaining GABA A Rs may be much higher than previously thought (21). In light of these findings, and the possible involvement of ␦ subunit-containing receptors in generating tonic conductances (8-11), we recorded from wild-type and ␦Ϫ͞Ϫ mice, and examined the effects of the naturally occurring neuroactive steroid 3␣,21-dihydroxy-5␣-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) on the tonic GABA A R-mediated conduct...

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“…For THDOC, recent estimates of the basal plasma concentration in male rats range from Ϸ5 to 8 nM (26)(27)(28), to nearly 20 nM after acute swim stress (26). As shown in Fig.…”

Section: Resultsmentioning

confidence: 91%

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors

Stell

Brickley

Tang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

743

793

View full text Add to dashboard Cite

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“…Interestingly, anxiogenic compounds such as beta-carbolines and caffeine produce increases in cortical neurosteroid levels (Barbaccia et al 1997;Concas et al 2000). Moreover, administration of anxiogenic and not anxiolytic doses of nicotine produce increases in brain allopregnanolone levels (Porcu et al 2003). Thus, it is conceivable that increasing brain allopregnanolone levels represent a physiological response to the anxiogenic effects of nicotine, caffeine and Δ9-THC.…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced levels of allopregnanolone in the CNS are thought to contribute to the therapeutic effects of several specific serotonin reuptake inhibitors (SSRIs) and various effects of ethanol (Uzunova et al 1998;VanDoren et al 2000;Khisti et al 2003). Moreover, several other pharmacological agents, including caffeine, nicotine, clozapine and olanzapine, produce elevated cortical allopregnanolone levels (Concas et al 2000;Marx et al 2000;Barbaccia et al 2001;Porcu et al 2003). In studies using naturally and artificially enhanced levels of allopregnanolone, some investigators suggest that altered allopregnanolone levels may be correlated with the rewarding effects of ethanol.…”

Section: Introductionmentioning

confidence: 99%

Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

et al. 2004

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“…Smoking also increases DHEA levels (Field et al, 1994;Feldman et al, 1998;Mendelson et al, 2005), and we have recently determined that serum levels of allopregnanolone are correlated with salivary levels of cotinine (a nicotine metabolite) in subjects with nicotine dependence (Marx et al, in press). Nicotine also elevates neuroactive steroid levels in rodent models (Porcu et al, 2003). Smoking status at the time of death is hence an important potential confounder, given high rates of nicotine dependence in patients with schizophrenia and bipolar disorder.…”

Section: Study Limitations and Potential Confounding Factorsmentioning

confidence: 99%

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

Marx

Stevens

Shampine

et al. 2005

Neuropsychopharmacol

159

125

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Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n ¼ 14-15 per group, 59-60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABA A and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.

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Nicotine-induced changes in cerebrocortical neuroactive steroids and plasma corticosterone concentrations in the rat

Cited by 62 publications

References 40 publications

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors

Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

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Nicotine-induced changes in cerebrocortical neuroactive steroids and plasma corticosterone concentrations in the rat

Cited by 62 publications

References 40 publications

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA A receptors

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA A receptors

Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

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Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors